Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., growth including survival, proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, schizophrenia, epilepsy and peripheral neuropathy and associated pain affect millions of people. It is the loss of normal neuronal function, which produces the behavioral and physical deficits which are characteristic of each of the different neurological disorders. In addition to chronic and acute neurodegenerative disorders, the aging process, physical trauma to the nervous system, and metabolic disorders may result in the loss, dysfunction, or degeneration of neural cells accompanied by the associated behavioral and physical deficits. Many of these diseases are today incurable, highly debilitating, and traditional drug therapies often fail. There is thus a great medical need for new therapeutic proteins that are disease modifying or for symptomatic use or both.
Several secreted factors with expression in the nervous system or associated target areas have important therapeutic uses in various neurological indications associated with reduction or loss of neuronal functions. E.g. NGF is a candidate for treatment of Alzheimer's disease, Neublastin (Artemin) a candidate for treatment of peripheral neuropathy, and GDNF is a candidate for treatment of Parkinson's Disease.
WO 93/22437 (Innogenetics) discloses a polypeptide which is identical to METRNL. It is suggested that the protein or its antagonist can be used as antitumor compounds, or anti-inflammatory compounds or as growth activators of T-cells and B-cells, as bone repair compounds as inducer of immunosuppressive cells, as inhibitors of anti-colony stimulating factor; or as trypanocidal agents.
WO 01/039786 (Innogenetics) discloses specific uses of polypeptides denominated as suppressive macrophage activation factors (SMAF's) wherein SMAF-1 is 100% identical to METRNL. Specifically, it is disclosed that SMAF-1 and/or SMAF-2 modulate the production of Th1, Th2 and/or Th3 cytokines and indicates how the latter molecules, nucleic acids encoding them and antibodies against them can be used to treat diseases mediated by type 1, type 2 and/or type 3 responses such as inflammation, infections, allergies, autoimmune diseases, transplant rejections, graft-versus-host disease, malignancies and diseases involving mucosal immunity.
METRNL is not described individually in the scientific literature. However, in a very large gene expression data set examining several tissues in different rat strains (Walker et al (2004). Applications of a rat multiple tissue gene expression data set. Genome Res. 14, 742-749), Meteorin-like is absent from the CNS and only detected in cornea, spleen, endothelial cells and intestines (GEO, GDS589/rc_A1639012_at). In the GNF SymAtlas v1.2.4, Meteorin-like is not reliably detected in any of the 60 mouse tissues examined (GFN1M, gnf1m08104_at).
It has been demonstrated that METRNL is one of several genes regulated by Pax2 and thereby expressed in the inner ear during development in Japanese killifish, medaka (Oryzias latipes) (Ramialison et al., Genome Biol. 2008 Oct. 1; 9(10):R145). The authors conclude that the Pax2 regulated genes are “novel otic vesicle specific genes, which are amenable to further functional analysis”.
WO 2005/095450 (NsGene) discloses NsG33 also known as Meteorin (METRN) and its use for treatment of neurological disorders or diseases. METRN is related to METRNL but the full length polypeptides share only 44% sequence identity. The expression of METRN is primarily restricted to the central nervous system and it has been shown to be active in several in vitro assays with primary and secondary neuronal cell types. Nishino et al (EMBO Journal (2004) 23, 1998-2008) also dicsloses METRN and its effects on regulation of glial cell differentiation and axonal extension.
While the prior art clearly indicates that METRN is a neurotrophic factor, METRNL has not been suggested for such uses. Based on the functional data available in WO 01/039786 and WO 93/22437 it would not be expected that METRNL would have any effect on the nervous system. The expression data available in the art also do not hint in this direction.